Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels affect such processes as nerve transmission, muscle contraction and cellular secretion. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nerve, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.
Potassium channels are membrane-spanning proteins that generally act to hyperpolarize neurons and muscle cells. Physiological studies indicate that potassium currents are found in most cells and are associated with a wide range of functions, including the regulation of the electrical properties of excitable cells. Depending on the type of potassium channel, its functional activity can be controlled by transmembrane voltage, different ligands, protein phosphorylation, or other second messengers (see, e.g., U.S. Pat. No. 6,893,858).
The potassium channel family possesses approximately seventy members in mammalian tissues. The recently identified KCNQ subfamily (Kv7) has been shown to play an important functional role as determinants of cell excitability. Recent evidence indicates that the KCNQ potassium channel sub-units form the molecular basis for M-current activity in several tissue types. This gene family has evolved to contain at least five major sub-units designated KCNQ1 through KCNQ5 (Kv7.1-7.5). These sub-units have been shown to co-assemble to form both heteromeric and homomeric functional ion channels.
Voltage dependant potassium channels are key regulators of the resting membrane potential and modulate the excitability of electrically active cells, such as neurons or myocytes. Several classes of voltage dependant potassium (K+) channels have been cloned (see, e.g., Lerche C et al., J. Biol. Chem. 275:22395-22400 (2000)).
Mutations in four of the five KCNQ potassium channel genes are implicated in diverse diseases, causing cardiac LQT syndrome (KCNQ1), epilepsy (KCNQ2, and 3), congenital deafness (KCNQ4). In rat genome, however, only four KCNQ channels have been identified.
Potassium channels are involved in a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport.
Herein, Applicants describe a novel gene, and uses for, the rat KCNQ5 (rKCNQ5) that has been identified from the expressed sequence tags (ESTs) using RT-PCR (reverse transcription-polymerase chain reaction) and RACE (rapid amplification of cDNA ends).